Submissions for variant NM_000051.4(ATM):c.2989G>A (p.Val997Ile)

dbSNP: rs1487902875

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701054	SCV000829836	uncertain significance	Ataxia-telangiectasia syndrome	2024-04-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 997 of the ATM protein (p.Val997Ile). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 578134). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000776861	SCV000912525	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 997 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATM-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000776861	SCV001178951	likely benign	Hereditary cancer-predisposing syndrome	2018-03-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV000776861	SCV005901830	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-08	criteria provided, single submitter	clinical testing	PM2_Supporting, BP4 c.2989G>A located in exon 20 of the ATM gene, is predicted to result in the substitution of valine by isoleucine at codon 997, p.(Val997Ile).It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score for this variant (0.135) suggests that it does not affect the protein function (BP4). In addition, the variant was also identified in the ClinVar (2x uncertain significance, 1x likely benign) but it has not been reported in LOVD database. Based on currently available information, the variant c.2989G>A is classified as an uncertain significance variant according to ClinGen-ATM Guidelines version v1.1.